Chloroquine (Nivaquine) was the first drug used for the treatment of malaria. It is effective against the blood stages of the malaria parasite and penetrates into most tissues. It is effective against Plasmodium ovale and malaria and susceptible strains of vivax and falciparum.

It may also be used for the prophylaxis of malaria in travelers visiting endemic areas. However, it is not effective in preventing relapse and should not be used in severe and complicated cases like cerebral malaria. It is also used to treat extraintestinal amebiasis and discoid lupus erythematosus (off-label use)

Chloroquine use in the COVID-19 infection (Wuhan Coronavirus infection - Nivaquine and Coronavirus):

Chloroquine phosphate has also been recommended in the treatment algorithm of Upper respiratory tract infection and pneumonia caused by COVID-19 infection (Wuhan Coronavirus infection). In COVID-19 infection (Wuhan Coronavirus infection), it is given with either oseltamivir or Darunavir. See chloroquine doses below.

Chloroquine dose in Adults

Note: 250 mg of chloroquine phosphate is equivalent to 150 mg of chloroquine base

Chloroquine dose for the chemoprophylaxis of malaria:

• 500 mg of chloroquine phosphate (300 mg base) once a week (on the same day each week).
• Initiate treatment one to two weeks before entering the endemic area and continue for four weeks after leaving it.

Chloroquine dose for the treatment of uncomplicated Malaria:

• 1000 mg (600 mg base) on day 1, followed by 500 mg (300 mg base) at 6, 24, and 48 hours after the first dose.
• Concomitant therapy with primaquine in patients with chloroquine-sensitive P.vivax and P.ovale is necessary.

Chloroquine dose for the treatment of Extraintestinal amebiasis:

• 1 gm (600 mg base) daily for two days followed by 500 mg daily (300 mg base) for at least 2 to 3 weeks in combination with an intestinal amebicide.

Chloroquine dose as off-label use in Lupus erythematosus:

• It is not considered as a first-line agent due to the potential retinal toxicity. The daily dose should not exceed 2.3 mg/kg/day.

Chloroquine phosphate dose in COVID-19 associated pneumonia:

• Chloroquine Phosphate 500 mg twice daily for 5 days plus Darunavir 800 mg/ Cobiestat 150 mg once daily for two weeks

Chloroquine phosphate dose in COVID-19 associated upper respiratory tract infection:

• 500 mg twice daily for 5 days Plus Oseltamivir 150 mg twice daily for five days.

Chloroquine dose in Childrens

Note: The dose is expressed as chloroquine phosphate. 16.6 mg of Chloroquine phosphate is equivalent to 10 mg chloroquine base.

• Dose for the Chemoprophylaxis of malaria

  • 8.3 mg/kg once a week (on the same day each week) to a maximum dose of 500 mg
  • Therapy should begin 1 to 2 weeks prior to entering the endemic area and continued for four weeks after leaving it [Ref]
  • Patients who delay initiating prophylaxis should take the double dose i.e. 16.6 mg/kg in two divided doses six hours apart and continue for eight weeks after leaving the endemic area.

• For the treatment of acute uncomplicated malarial infection [Ref]:

  • 16.6 mg/kg to a maximum initial dose of 1,000 mg chloroquine phosphate followed by 8.3 mg/kg to a maximum dose of 500 mg/dose administered at 6, 24, and 48 hours after the initial dose for a total of 4 doses.

• Treatment of Extraintestinal amebiasis and liver abscess:

  • Children and Adolescents:
    • 16.6 mg/kg//dose once a day in combination with metronidazole or tinidazole for 21 days followed by paromomycin or iodoquinol to a maximum dose of 1,000 mg/dose.

Pregnancy Risk Factor C

• However, there have been no adverse outcomes for fetal health after Chloroquine crosses into the placenta.
• Pregnancy malaria is more serious than usual, so it should be treated promptly. 
• If not treated promptly, it can increase the risk of stillbirth, spontaneous abortion, and prematurity.
• Women who are pregnant in non-endemic regions should not travel to endemic zones or use the appropriate prophylaxis.
• Pregnant females with uncomplicated malaria caused by chloroquine-sensitive P. vivax or P. ovale should be treated with chloroquine. 
• Pregnant women with malaria should be treated until they give birth. It can be used in all trimesters of pregnancy [Ref].

Use during breastfeeding:

• It is compatible with breastfeeding for women who have autoimmune rheumatic or malaria-related maladies.
• Premature infants, especially, should be closely monitored for hemolysis or jaundice. 
• Breastfeeding should be avoided in infants with G6PD deficiency [Ref].
• If breastfed babies are exposed to maternal chlorine, they should be treated with the appropriate antimalarials.
• Breastfeeding infants can contract the disease from maternal drug excretion in breastmilk.

Chloroquine dose in Renal Disease:

The manufacturer has not recommended any dose adjustment, however, dosing in patients with renal impairment should follow the following guidelines [Ref]:

• Patients with an eGFR of more than 10 ml/min do not require any dose adjustment
• eGFR of less than 10 ml//min, those on hemodialysis, and peritoneal dialysis should take half the recommended dose.
• Dose adjustment is not required in patients with Continuous renal replacement therapy (CRRT).

Dose in Liver disease:

• Use with caution in patients with liver disease.
• The manufacturer has not recommended any dose adjustment in patients with liver disease.

Common Side Effects of chloroquine:

• Cardiovascular:

  • Atrioventricular block
  • Bundle branch block
  • Cardiac arrhythmia
  • Cardiomyopathy
  • ECG changes including prolonged QRS and QTc intervals, T-wave inversion, or depression
  • Hypotension
  • Torsades de pointes
  • Ventricular fibrillation
  • Ventricular tachycardia

• Central nervous system:

  • Agitation
  • Anxiety
  • Confusion
  • Depressed deep tendon reflex
  • Delirium
  • Depression
  • Extrapyramidal reactions like dystonia, dyskinesia, and protrusion of the tongue, torticollis),
  • Hallucination
  • Headache
  • Insomnia
  • Motor dysfunction
  • Personality changes
  • Polyneuropathy
  • Psychosis
  • Seizure
  • Suicidal tendencies

• Dermatologic:

  • Alopecia
  • Bleaching of hair
  • Blue-gray skin pigmentation
  • Erythema multiforme
  • Exacerbation of psoriasis
  • Exfoliative dermatitis
  • Lichen planus
  • Pleomorphic rash
  • Pruritus
  • Skin
  • Photosensitivity
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Urticaria

• Endocrine & metabolic:

  • Hypoglycemia

• Gastrointestinal:

  • Abdominal cramps
  • Anorexia
  • Diarrhea
  • Nausea
  • Vomiting

• Hematologic & oncologic:

  • Reversible Agranulocytosis
  • Aplastic anemia
  • Hemolytic anemia especially in G6PD-deficient patients
  • Neutropenia
  • Pancytopenia
  • Thrombocytopenia

• Hepatic:

  • Hepatitis
  • Increased liver enzymes

• Hypersensitivity:

  • Anaphylactoid reaction
  • Anaphylaxis
  • Angioedema

• Immunologic:

  • DRESS syndrome

• Neuromuscular & skeletal:

  • Myopathy
  • Neuromuscular disease
  • Proximal myopathy

• Ophthalmic:

  • Accommodation disturbances
  • Blurred vision
  • Reversible Corneal opacification
  • Irreversible Macular degeneration
  • Maculopathy which may be irreversible
  • Nocturnal amblyopia
  • Retinopathy (may be irreversible in some patients on long term therapy)
  • Transient scotomata
  • Visual field defects

• Otic:

  • Sensorineural Deafness
  • Hearing loss especially in patients with preexisting auditory damage
  • Tinnitus

Contraindications to Chloroquine use include:

• Allergy to the drug or 4-aminoquinolines or any component of its formulation
• For indications other that acute malaria, retinal or visual field changes may be indicated.

Warnings and Precautions

• Cardiovascular effects

  • Chloroquine long-term use can cause cardiomyopathy, especially if taken in high doses.
  • Patients should be closely monitored for signs and symptoms of heart disease.
  • If the patient develops Atrioventricular or bundle branch block, it should be stopped immediately.
  • It has been associated with QT prolongation, Torsade de Pointes and sometimes fatal ventricular arrhythmias.
  • Patients at high risk for arrhythmias such as hypokalemia, hypomagnesemia and bradycardia should be cautious when using it.
  • According to the American Heart Association, it may cause direct myocardial toxicity and exacerbate underlying myocardial dysfunction [Ref]

• Extrapyramidal effects:

  • Extrapyramidal effects may occur in patients who are treated.

• Hematologic effects

  • Rarely, patients may experience severe hematologic reactions, including reversible anemia, aplastic and neutropenia, neutropenia, pancytopenia, thrombocytopenia, or aplastic anemia. 
  • Patients on long-term therapy should monitor their CBC.

• Hypoglycemia:

  • Hypoglycemia is a serious condition that can lead to death, especially for patients who are already taking anti-diabetic medications. 
  • It is possible to have fatal hypoglycemias, which can be symptomatic and lead to loss of consciousness.

• Neuromuscular effects:

  • Myopathy characterized by progressive muscle weakness has been reported. Muscular weakness should be checked on a regular basis.
  • If muscle weakness continues, treatment may be stopped.

• Toxicity to the retina:

  • Patients who have been exposed to high doses of vitamin A for more than five years may develop irreversible retinopathy.
  • Retinal toxicity is also more likely in patients with kidney impairment, low body mass, and concomitant use of tamoxifen.
  • American Academy of Ophthalmology (AAO), recommends a daily maximum dose of 2.3 mg/kg of body weight.
  • Screening for retinal toxicity at baseline and annually after five years of use is recommended by the AAO [Ref].

• Auditory damage

  • Hearing loss can occur in patients with existing auditory damage. If toxicity occurs, it is important to stop all therapy immediately.

• G6PD deficiency:

  • G6PD deficiency patients with mild to moderate levels should be cautious about using the drug.
  • The safety of its use in patients with severe hemolytic anemia is not known [Ref].

• Hepatic impairment

  • It should be used with caution for patients with liver disease, who have had a history of drinking and those taking concurrent hepatotoxic medications.

• Porphyria

  • It can worsen symptoms of porphyria.

• Psoriasis:

  • It can exacerbate psoriasis symptoms and should be taken with caution.

• Seizure disorder:

  • Patients with seizure disorders should use it with caution.

Chloroquine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitor:

• Patients who are receiving prolonged therapy should periodically monitor Blood CBC and neuromuscular function.
• An eye exam at baseline and periodically to screen for retinal toxicity should be carried out.
• Fundus examination plus visual fields and spectral-domain optical coherence tomography [SD OCT] if maculopathy is present at baseline and annually after 5 years of its use or more frequent should be done especially in patients at risk. 

How to administer Chloroquine?

• It should be taken with meals to reduce GI upset.
• Since it is very bitter, some of the formulations have been prepared as gelatin capsules while others have mixed it with chocolate-flavored preparations. 

Mechanism of action Chloroquine:

• It inhibits the metabolism of parasites and hemoglobin utilization by binding to and inhibiting DNA and RNA polymerase.
• It is also found in the parasite vesicles, where it interferes with the parasite's acid-base balance.
• This inhibits the growth of the parasite. It can also cause membrane damage and interfere with nucleoprotein production.

The mechanism of chloroquine in the treatment of Coronavirus infection is discussed here - "Antimalarial drug revives the hope to treat infections caused by Coronavirus infections" It happens quickly and almost immediatelyabsorbedIt is found in many body tissues, including the eyes, liver, kidneys, liver, leukocytes and lungs.

Nearly half of it is.protein-bound.It isMetabolizedBy the liver to desethylchloroquine It has a half life ofIt takes between 3 and 5 days for the peak serum concentration to be reached after oral ingestion. It is mostly excreted through urine.

International brands of Chloroquine Phosphate:

• A-CO
• Alexoquine
• Antimal
• Aralen
• Aralen Phosphate
• Arechin
• Arquin
• Avloclor
• Avloquin
• Bidimalaquin
• Cadiquin
• Chemochin
• Chlorochin
• Chlorofoz
• Chloromax
• Chlorquin
• Clit
• Clo-Kit Junior
• Clorochina Bayer
• Clorochina Bifosfato
• Crocan
• Delagil
• Demoquine
• Dichinalex
• Diroquine
• Heliopar
• Heroquine
• Klarquine
• Klorokinfosfat
• Lagaquin
• Malachlo
• Malaquin
• Malarex
• Malarivon
• Malarquine
• Malaviron
• Malquin
• Maquine
• Nivaquine
• Paludol
• Quinacris
• Resochin
• Resochina

Chloroquine brand names in Pakistan: